tbuckley/cabot-search huggingface dataset:
Simultaneous control of infection and inflammation with keratin-derived antibacterial peptides targeting TLRs and co-receptors
Authors: Yan Sun, Jonathan Chan, Karthikeyan Bose, Connie Tam
Journal: Science Translational Medicine (2023)

Controlling infection-driven inflammation is a major clinical dilemma because of limited therapeutic options and possible adverse effects on microbial clearance. Compounding this difficulty is the continued emergence of drug-resistant bacteria, where experimental strategies aiming to augment inflammatory responses for enhanced microbial killing are not applicable treatment options for infections of vulnerable organs. As with corneal infections, severe or prolonged inflammation jeopardizes corneal transparency, leading to devastating vision loss. We hypothesized that keratin 6a–derived antimicrobial peptides (KAMPs) may be a two-pronged remedy capable of tackling bacterial infection and inflammation at once. We used murine peritoneal neutrophils and macrophages, together with an in vivo model of sterile corneal inflammation, to find that nontoxic and prohealing KAMPs with natural 10– and 18–amino acid sequences suppressed lipoteichoic acid (LTA)– and lipopolysaccharide (LPS)–induced NFκB and IRF3 activation, proinflammatory cytokine production, and phagocyte recruitment independently of their bactericidal function. Mechanistically, KAMPs not only competed with bacterial ligands for cell surface Toll-like receptor (TLR) and co-receptors (MD2, CD14, and TLR2) but also reduced cell surface availability of TLR2 and TLR4 through promotion of receptor endocytosis. Topical KAMP treatment effectively alleviated experimental bacterial keratitis, as evidenced by substantial reductions of corneal opacification, inflammatory cell infiltration, and bacterial burden. These findings reveal the TLR-targeting activities of KAMPs and demonstrate their therapeutic potential as a multifunctional drug for managing infectious inflammatory disease.
Cancer Treatment-Related Ovarian Dysfunction in Women of Childbearing Potential: Management and Fertility Preservation Options
Authors: Anna C. Reynolds, Laurie J. McKenzie
Journal: Journal of Clinical Oncology (2023)

PURPOSE To review the complex concerns of oncofertility created through increased cancer survivorship and the long-term effects of cancer treatment in young adults. DESIGN Review chemotherapy-induced ovarian dysfunction, outline how fertility may be addressed before treatment initiation, and discuss barriers to oncofertility treatment and guidelines for oncologists to provide this care to their patients. CONCLUSION In women of childbearing potential, ovarian dysfunction resulting from cancer therapy has profound short- and long-term implications. Ovarian dysfunction can manifest as menstrual abnormalities, hot flashes, night sweats, impaired fertility, and in the long term, increased cardiovascular risk, bone mineral density loss, and cognitive deficits. The risk of ovarian dysfunction varies between drug classes, number of received lines of therapy, chemotherapy dosage, patient age, and baseline fertility status. Currently, there is no standard clinical practice to evaluate patients for their risk of developing ovarian dysfunction with systemic therapy or means to address hormonal fluctuations during treatment. This review provides a clinical guide to obtain a baseline fertility assessment and facilitate fertility preservation discussions.
Earthquakes in Turkey and Syria—collaboration is needed to mitigate longer terms risks to health
Authors: Erva Nur Cinar, Aula Abbara, Ebru Yilmaz
Journal: BMJ (2023)

The catastrophic earthquakes that struck southeastern Turkey and northern Syria on 6 February 2023 left a humanitarian crisis in their wake.As of 1 March 2023, the death toll in Turkey has risen to 45 089, and 6000 deaths have been reported in Syria. 1 2 It is likely, however, that the death toll and the extent of the damage will continue to rise-particularly in northwest Syria where search and rescue efforts have been impeded by border restrictions.Much of the immediate devastation is apparent, but without careful mitigation, the people of these two countries will experience more insidious, longer term harms to their health.
Inhibitory Control Training Enhanced by Transcranial Direct Current Stimulation to Reduce Binge Eating Episodes: Findings from the Randomized Phase II ACCElect Trial
Authors: Katrin E. Giel, Kathrin Schag, Sebastian M. Max, Peter Martus, Stephan Zipfel, Andreas J. Fallgatter, Christian Plewnia
Journal: Psychotherapy and Psychosomatics (2023)

Binge eating disorder (BED) is characterized by recurrent binge eating (BE) episodes with loss of control. Inhibitory control impairments, including alterations in dorsolateral prefrontal cortex (dlPFC) functioning, have been described for BED. A targeted modulation of inhibitory control circuits by the combination of inhibitory control training and transcranial brain stimulation could be promising.The aim of the study was to demonstrate feasibility and clinical effects of a transcranial direct current stimulation (tDCS)-enhanced inhibitory control training to reduce BE episodes and to generate an empirical basis for a confirmatory trial.We performed a monocentric clinical phase II double-blind randomized trial with two parallel arms. Forty-one adult outpatients with full-syndrome BED according to DSM-5 received six sessions of food-related inhibitory control training, randomly combined with 2 mA verum or sham tDCS of the right dlPFC. The main outcome was BE frequency within a 4-week interval after treatment termination (T8; primary) and at 12-week follow-up (T9; secondary) as compared to baseline.BE frequency was reduced in the sham group from 15.5 to 5.9 (T8) and to 6.8 (T9); in the verum group, the reduction was 18.6 to 4.4 (T8) resp. 3.8 (T9). Poisson regression with the study arm as the factor and baseline BE frequency as the covariate revealed a p value of 0.34 for T8 and 0.026 for T9. Sham and real tDCS differed at T9 in BE frequency.Inhibitory control training enhanced by tDCS is safe in patients with BED and results in a substantial and sustainable reduction in BE frequency which unfolds over several weeks post-treatment. These results constitute the empirical basis for a confirmatory trial.
Phase 2 Trial of Stereotactic Ablative Radiotherapy for Patients with Primary Renal Cancer
Authors: Raquibul Hannan, Mark F. McLaughlin, Laurentiu M. Pop, Ivan Pedrosa, Payal Kapur, Aurelie Garant, Chul Ahn, Alana Christie, James Zhu, Tao Wang, Liliana Robles, Deniz Durakoglugil, Solomon Woldu, Vitaly Margulis, Jeffrey Gahan, James Brugarolas, Robert Timmerman, Jeffrey Cadeddu
Journal: European Urology (2023)
Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.
Authors: Aisha Jibril, Charlotte Hellmich, Edyta Wojtowicz, Katherine Hampton, Rebecca S Maynard, Ravindu De Silva, Dominic J Fowler-Shorten, Jayna J. Mistry, Jamie A Moore, Kristian M Bowles, Stuart A Rushworth
Journal: Blood (2023)

Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites and DNA and have various context specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognised via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma and cancer patients, however the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in-vivo models, we describe the role of MM cell derived mtDAMPs in the pro-tumoral BM microenvironment, and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of MM patients compared to healthy controls. Using the MM1S cells engrafted into NSG mice we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the STING pathway and inhibition of this pathway reduces MM tumor-burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signalling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the pro-tumoral BM microenvironment.
Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study
Authors: David A. Sallman, Monzr M. Al Malki, Adam S. Asch, Eunice S. Wang, Joseph G. Jurcic, Terrence J. Bradley, Ian W. Flinn, Daniel A. Pollyea, Suman Kambhampati, Tiffany N. Tanaka, Joshua F. Zeidner, Guillermo Garcia-Manero, Deepa Jeyakumar, Rami Komrokji, Jeffrey Lancet, Hagop M. Kantarjian, Lin Gu, Yajia Zhang, Anderson Tan, Mark Chao, Carol O'Hear, Giridharan Ramsingh, Indu Lal, Paresh Vyas, Naval G. Daver
Journal: Journal of Clinical Oncology (2023)

Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479).
Let’s talk about sex (and gender) after ACL injury: a systematic review and meta-analysis of self-reported activity and knee-related outcomes
Authors: Andrea M Bruder, Adam G Culvenor, Matthew G King, Melissa Haberfield, Eliza A Roughead, John Mastwyk, Joanne L Kemp, Marcella Ferraz Pazzinatto, Thomas J West, Sally L Coburn, Sallie M Cowan, Allison M Ezzat, Laura To, Karina Chilman, Jamon L Couch, Jackie L Whittaker, Kay M Crossley
Journal: British Journal of Sports Medicine (2023)

Objective Investigate sex/gender differences in self-reported activity and knee-related outcomes after anterior cruciate ligament (ACL) injury. Design Systematic review with meta-analysis. Data sources Seven databases were searched in December 2021. Eligibility criteria Observational or interventional studies with self-reported activity (including return to sport) or knee-related outcomes after ACL injury. Results We included 242 studies (n=123 687, 43% females/women/girls, mean age 26 years at surgery). One hundred and six studies contributed to 1 of 35 meta-analyses (n=59 552). After ACL injury/reconstruction, very low-certainty evidence suggests females/women/girls had inferior self-reported activity (ie, return to sport, Tegner Activity Score, Marx Activity Scale) compared with males/men/boys on most (88%, 7/8) meta-analyses. Females/women/girls had 23%–25% reduced odds of returning to sport within 1-year post-ACL injury/reconstruction (12 studies, OR 0.76 95% CI 0.63 to 0.92), 1–5 years (45 studies, OR 0.75 95% CI 0.69 to 0.82) and 5–10 years (9 studies, OR 0.77 95% CI 0.57 to 1.04). Age-stratified analysis (&lt;19 years) suggests female athletes/girls had 32% reduced odds of returning to sport compared with male athletes/boys (OR 0.68, 95% CI 0.41 to 1.13, I 2 0.0%). Very low-certainty evidence suggests females/women/girls experienced inferior knee-related outcomes (eg, function, quality of life) on many (70%, 19/27) meta-analyses: standardised mean difference ranging from −0.02 (Knee injury and Osteoarthritis Outcome Score, KOOS-activities of daily living, 9 studies, 95% CI −0.05 to 0.02) to −0.31 (KOOS-sport and recreation, 7 studies, 95% CI −0.36 to –0.26). Conclusions Very low-certainty evidence suggests inferior self-reported activity and knee-related outcomes for females/women/girls compared with males/men/boys after an ACL injury. Future studies should explore factors and design targeted interventions to improve outcomes for females/women/girls. PROSPERO registration number CRD42021205998.
Update on C-Cell Neuroendocrine Neoplasm: Prognostic and Predictive Histopathologic and Molecular Features of Medullary Thyroid Carcinoma
Authors: Chan Kwon Jung, Shipra Agarwal, Jen-Fan Hang, Dong-Jun Lim, Andrey Bychkov, Ozgur Mete
Journal: Endocrine Pathology (2023)
Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer
Authors: Feda H Hamdan, Amro M Abdelrahman, Ana Patricia Kutschat, Xin Wang, Thomas L Ekstrom, Nidhi Jalan-Sakrikar, Catherine Wegner Wippel, Negar Taheri, Liezel Tamon, Waltraut Kopp, Joana Aggrey-Fynn, Aditya V Bhagwate, Roberto Alva-Ruiz, Isaac Lynch, Jennifer Yonkus, Robyn Laura Kosinsky, Jochen Gaedcke, Stephan A Hahn, Jens T Siveke, Rondell Graham, Zeynab Najafova, Elisabeth Hessmann, Mark J Truty, Steven A Johnsen
Journal: Gut (2023)

Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC.iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.
Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression
Authors: Sofia Bruni, Florencia L Mauro, Cecilia J Proietti, Rosalia I Cordo-Russo, Martin A Rivas, Gloria Inurrigarro, Agustina Dupont, Dario Rocha, Elmer A Fernández, Ernesto Gil Deza, Daniel Lopez Della Vecchia, Sabrina Barchuk, Silvina Figurelli, David Lasso, Adrián D Friedrich, María C Santilli, María V Regge, Gabriel Lebersztein, Claudio Levit, Fabiana Anfuso, Teresa Castiglione, Patricia V Elizalde, Maria F Mercogliano, Roxana Schillaci
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion. Methods We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes. Results In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors. Conclusions These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.
JAMA Cardiology
Authors: Patrick O'gara, Marc Sabatine, Clyde Boston, Ann Yancy, Michael Pencina, Carolina North, Robert Harrington, Adrian Hernandez, Mhs Durham, North Carolina, Ajay Kirtane, New York, Roxana Mehran, Pradeep Natarajan, Kristen Boston, Seattle Patton, Washington Udelson, Sadiya Khan, Gregg Fonarow, Los Angeles, Sharlene Day, Laine Thomas, Akhil Narang, Julia Getts, Eugene Braunwald, Judith Hochman, Donald Lloyd-Jones, Scm Chicago, Michael Parmacek, Daniel Simon, Sidney Smith, Chapel Hill, Carolina Douglas, E Vaughan, Myron Weisfeldt, Maryland Douglas, P Zipes, Paul Armstrong, Shinya Goto, Peter Liu, Renato Lopes, Carolina Prabhakaran, Hugh Watkins, Harvey White, Habib Yacoub, Frs London, Gregory Curfman, Annette Flanagin, Michael Berkwits, Brenda Gregoline, Tracy Frey, Iris Lo, Kevin Brown, Bernadette Hromin, Erin Keenan, Rebecca Langley, Kris Simmons, Connie Manno, Sara Billings, Doug Brandt, Timothy Gray, Peter Olson, Juliet Orellana, Paul Ruich, Kirby Snell, Judith Ahlers, Stephanie Beckmeyer, Dawn Bielawski, Jane Calayag, Jan Clavey, Mary Coerver-Connolly, Amy Eutsey, Paul Jaworski, Laura King, Martha Lentz, Jenny Mackay, Jennifer Maybin, Charon Pierson, Shilpa Shenvi, Thressa Smith, Divya Sreekumar, Donna Thordsen, Christine Tilles, Emma Underdown, Cara Wallace, Becki Weiss, Christina West, Caroline Woods, Erin Kato, Jacob Kendall-Taylor, Monica Mungle, Lenette Gardner-Gullens, Anna Bukowski, Lee Calibeo, Jordan Faber, Andrew Given, Tosca Hall, Emma Hyche, Kenneth Otani, Caroline Sietmann, Angelia Digital, Elena Guobyte, Daniel Morrow, Shelly Steff, Jennifer Zeis, Jim Michalski, Eman Aly, Reuben Rios, Mary Ferkaluk, Sidra Bonner, Heather Hsu, Andrew Ibrahim, Karen Bucher, Andy Rekito, Nick Reback, Lohitha Kethu, Marla Erson, Joseph Thornton, Thomas Easley, Brian Shields, Karen Adams-Taylor, Paul Gee, Anna Frazier, Monica Smith, Julie Burton, Ronna Hewitt, Mary Sieck, Geneine Someren, Jamaal Vargas, Content Systems, Mike Bujewski, Nathan Mitre, Digital Production, Regina Brownlee, Amanda Camino, Brenda Chandler-Grayer, Emily Dunn, Amy Evers, Maleeka Holden, Teri Hutchison, Dan Knowles, Joshua Lampinen, Natalie Marsh, Patricia Panek, Marla Seidell, La Son, Diggs Sledge, Julian Graphics, Joe Amft, Jonathan Chala, Maria Duda, Fred Furtner, Carolyn Hall, Maria Kowalkowski, Kelley Mcdonald, Joy Farrell, Maria Giannini, Sasha Grossman, Kate Lander, Judith Literskis, Teresa Omiotek, Michael Ryder, James Madara, Kirsten Bibbins-Domingo, Robert Bonow
Journal: JAMA Cardiology (2023)

science, and evidence-based health policy.Health equity, especially when supported by original science, is a leading editorial priority.
Sphingolipids and impaired hypoxic stress responses in Huntington disease
Authors: Johannes Burtscher, Giuseppe Pepe, Niran Maharjan, Nathan Riguet, Alba Di Pardo, Vittorio Maglione, Grégoire P. Millet
Journal: Progress in Lipid Research (2023)

Huntington disease (HD) is a debilitating, currently incurable disease. Protein aggregation and metabolic deficits are pathological hallmarks but their link to neurodegeneration and symptoms remains debated. Here, we summarize alterations in the levels of different sphingolipids in an attempt to characterize sphingolipid patterns specific to HD, an additional molecular hallmark of the disease. Based on the crucial role of sphingolipids in maintaining cellular homeostasis, the dynamic regulation of sphingolipids upon insults and their involvement in cellular stress responses, we hypothesize that maladaptations or blunted adaptations, especially following cellular stress due to reduced oxygen supply (hypoxia) contribute to the development of pathology in HD. We review how sphingolipids shape cellular energy metabolism and control proteostasis and suggest how these functions may fail in HD and in combination with additional insults. Finally, we evaluate the potential of improving cellular resilience in HD by conditioning approaches (improving the efficiency of cellular stress responses) and the role of sphingolipids therein. Sphingolipid metabolism is crucial for cellular homeostasis and for adaptations following cellular stress, including hypoxia. Inadequate cellular management of hypoxic stress likely contributes to HD progression, and sphingolipids are potential mediators. Targeting sphingolipids and the hypoxic stress response are novel treatment strategies for HD.
Neuronal protein interaction networks in autism spectrum disorder
Authors: Lucy K. Bicks, Katherine Wade Eyring, Daniel H. Geschwind
Journal: Cell Genomics (2023)

How rare protein-disrupting risk variants implicated in autism spectrum disorders (ASDs) interact or functionally converge is unknown. Pintacuda et al.1 perform proteomics in induced human neurons and identify more than 1,000 interactions, 90% of which were not previously reported, emphasizing the importance of cell-type- and isoform-specific protein interactions in ASD.
Leveraging our common African origins to understand human evolution and health
Authors: Ambroise Wonkam, Adebowale Adeyemo
Journal: Cell Genomics (2023)

In the March 2023 issue of Cell, Fan et al.1 report whole-genome sequencing across 12 indigenous African populations and analyze local adaptation and evolutionary history. Here, Wonkam and Adeyemo highlight their findings and how this contributes to African and global genomic research.